文章：

泛素和泛素样蛋白在癌症发病中的作用

Ubiquitin and ubiquitin-like proteins in cancer pathogenesis

原文发布日期：2006-10-01

DOI: 10.1038/nrc1994

类型: Review Article

开放获取: 否

要点：

1. Ubiquitin is an 8 kDa polypeptide that can be covalently attached to other proteins through a process called ubiquitylation (also known as ubiquitination). Similar to phoshporylation, ubiquitylation is an inducible and reversible process that changes the properties of the modified substrate; for example, its subcellular localization, stability or enzymatic activity.
2. The attachment of ubiquitin to substrates requires the sequential action of three enzymes: ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2) and ubiquitin ligase (E3). This process can be reversed by de-ubiquitylating enzymes (DUBs) that remove ubiquitin from substrates.
3. Several ubiquitin-like modifiers (Ubls) have been identified, such as SUMO, NEDD8, ISG15 and FAT10. They possess a distinct primary sequence but share characteristic features with ubiquitin, including the 3-dimensional fold and the mode of their conjugation to substrates.
4. Protein domains that bind to ubiquitin (UBDs) or Ubls have crucial roles in the recognition of modified proteins and the translation of the encoded information into the proper cellular response. Most UBD-containing proteins undergo monoubiquitylation themselves, which causes their auto-inhibition by intramolecular UBD–ubiquitin interactions.
5. Alterations to the ubiquitin and Ubl systems are associated with various pathologies, such as inflammatory diseases and cancer. Moreover, many disease-related pathways are not only regulated by a single ubiquitin or Ubl, but by a sophisticated cross-talk of different types of modifications.
6. Examples of such ubiquitin or Ubl interplays in oncogenic pathways include p53, nuclear factor κB and DNA repair pathways, which are regulated by monoubiquitylation, polyubiquitylation, sumoylation and neddylation.
7. Bortezomib is the first compound that targets the ubiquitin-system to be approved for clinical use in human cancers. It inhibits the active site of one of the proteasome subunits and shuts down the proteasomal protein-degradation system.
8. New, more specific anticancer drugs that target the ubiquitin-system are being developed, including selective inhibitors of E3 enzymes like MDM2. Moreover, DUBs and the binding interface of ubiquitylated proteins and UBDs have emerged as promising drug targets.

要点翻译：

1. 泛素是一种8 kDa的多肽，可通过称为泛素化（ubiquitylation）的过程共价连接至其他蛋白质。与磷酸化类似，泛素化是一种可诱导且可逆的过程，能够改变修饰底物的特性，例如其亚细胞定位、稳定性或酶活性。
2. 将泛素连接至底物需要三种酶的依次作用：泛素激活酶（E1）、泛素结合酶（E2）和泛素连接酶（E3）。这一过程可被去泛素化酶（DUBs）逆转，该类酶能够从底物上移除泛素。
3. 目前已鉴定出多种泛素样修饰蛋白（Ubls），例如SUMO、NEDD8、ISG15和FAT10。它们具有独特的初级序列，但与泛素共享特征性结构，包括三维折叠方式以及与底物结合的模序。
4. 结合泛素（UBDs）或泛素样修饰蛋白的结构域在识别修饰蛋白并将编码信息转化为适当的细胞反应中发挥关键作用。大多数含UBD结构域的蛋白自身会发生单泛素化，通过分子内UBD-泛素相互作用导致自抑制。
5. 泛素和泛素样修饰系统的改变与多种病理状态相关，例如炎症性疾病和癌症。此外，许多疾病相关通路不仅受单一泛素或泛素样修饰蛋白的调控，还受到不同类型修饰间复杂相互作用的精细调节。
6. 致癌通路中泛素或泛素样修饰蛋白相互作用的实例包括p53、核因子κB和DNA修复通路，这些通路受单泛素化、多聚泛素化、类泛素化（sumoylation）和neddylation等修饰方式的调控。
7. 硼替佐米是首个针对泛素系统获批用于人类癌症临床治疗的化合物。它通过抑制蛋白酶体某个亚基的活性位点，从而阻断蛋白酶体的蛋白质降解系统。
8. 目前正在研发针对泛素系统的更新、更具特异性的抗癌药物，包括MDM2等E3酶的选择性抑制剂。此外，去泛素化酶以及泛素化蛋白与UBD结构域的相互作用界面已成为具有前景的药物靶点。

英文摘要：

Ubiquitin and ubiquitin-like proteins (Ubls) are signalling messengers that control many cellular functions, such as cell proliferation, apoptosis, the cell cycle and DNA repair. It is becoming apparent that the deregulation of ubiquitin pathways results in the development of human diseases, including many types of tumours. Here we summarize the common principles and specific features of ubiquitin and Ubls in the regulation of cancer-relevant pathways, and discuss new strategies to target ubiquitin signalling in drug discovery.

摘要翻译： 

泛素和类泛素蛋白（Ubls）是调控多种细胞功能（如细胞增殖、凋亡、细胞周期和DNA修复）的信号信使。越来越多的证据表明，泛素通路的失调会导致人类疾病的发生，包括多种肿瘤。本文总结了泛素和Ubls在调控癌症相关通路中的共同原理和特异性特征，并讨论了在药物研发中靶向泛素信号传导的新策略。

原文链接：

Ubiquitin and ubiquitin-like proteins in cancer pathogenesis